Targeting CLPTM1L for treatment and prevention of cancer
Inventors
Assignees
Publication Number
US-12129305-B2
Publication Date
2024-10-29
Expiration Date
2039-10-15
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Abstract
Provided herein are therapeutic agents having specificity for human CLPTM1L/CRR9 polypeptide, including therapeutic agents comprising one or more CLPTM1L-targeting agents, compositions comprising such therapeutic agents, and methods of using such compositions for treating or preventing a cancer, pre-cancerous lesion, or other disease condition associated with CLPTM1L/CRR9 protein dysfunction (e.g., pathogenic production, modification, or function). In particular, provided herein are fully human monoclonal antibodies against human CLPTM1L/CRR9 protein and methods of using such antibodies for treating or preventing a cancer, pre-cancerous lesion, or other disease condition associated with CLPTM1L/CRR9 protein dysfunction (e.g., pathogenic production, modification, or function).
Core Innovation
The invention provides therapeutic agents with specificity for human CLPTM1L/CRR9 polypeptide, especially fully human monoclonal antibodies against human CLPTM1L/CRR9 protein. These antibodies, their compositions, and related methods are designed for treating or preventing cancer, pre-cancerous lesions, or disease conditions associated with CLPTM1L/CRR9 protein dysfunction, such as pathogenic production, modification, or function.
The problem addressed by this invention is the need for methods to treat or prevent cancer, particularly methods capable of slowing or reducing tumor growth and preventing metastasis. Cancer involves mutation of oncogenes and tumor suppressor genes, leading to uncontrolled cell proliferation. Tumor survival and metastasis require resistance to mechanisms like apoptosis and anoikis; the invention targets CLPTM1L to interfere with these survival pathways.
The invention is based on the discovery that CLPTM1L is commonly over-expressed in certain cancers and protects tumor cells from genotoxic apoptosis. The monoclonal antibodies provided target specific extracellular epitopes of the CLPTM1L protein, leading to modulation of survival signaling pathways (such as Bcl-xL and Akt), chemosensitization, and inhibition of anchorage-independent tumor cell growth. These agents can be used alone or in combination with chemotherapeutic agents to enhance therapeutic efficacy.
Claims Coverage
The patent includes one independent claim, which discloses five main inventive features involving specific CLPTM1L-binding antibodies and their compositions.
Isolated antibody binding to human CLPTM1L with defined CDRs
An isolated antibody, or an antigen binding fragment thereof, is defined by its specific capability to bind human CLPTM1L. The antibody comprises either: - a heavy chain variable region with CDRH1 of SEQ ID NO:36, CDRH2 of SEQ ID NO:37, CDRH3 of SEQ ID NO:38 and a light chain variable region with CDRL1 of SEQ ID NO:39, CDRL2 of SEQ ID NO:40, and CDRL3 of SEQ ID NO:41; - a heavy chain variable region with CDRH1 of SEQ ID NO:42, CDRH2 of SEQ ID NO:43, CDRH3 of SEQ ID NO:44 and a light chain variable region with CDRL1 of SEQ ID NO:45, CDRL2 of SEQ ID NO:46, and CDRL3 of SEQ ID NO:47; - a heavy chain variable region with CDRH1 of SEQ ID NO:48, CDRH2 of SEQ ID NO:49, CDRH3 of SEQ ID NO:50 and a light chain variable region with CDRL1 of SEQ ID NO:51, CDRL2 of SEQ ID NO:52, and CDRL3 of SEQ ID NO:53; - a heavy chain variable region with CDRH1 of SEQ ID NO:54, CDRH2 of SEQ ID NO:55, CDRH3 of SEQ ID NO:56 and a light chain variable region with CDRL1 of SEQ ID NO:57, CDRL2 of SEQ ID NO:58, and CDRL3 of SEQ ID NO:59; - or a heavy chain variable region with CDRH1 of SEQ ID NO:60, CDRH2 of SEQ ID NO:61, CDRH3 of SEQ ID NO:62 and a light chain variable region with CDRL1 of SEQ ID NO:63, CDRL2 of SEQ ID NO:64, and CDRL3 of SEQ ID NO:65.
Human antibody composition with defined light and heavy chain sequences
A human antibody composition, where the antibody comprises: - a light chain having SEQ ID NO:26 or at least 85% sequence identity thereto and a heavy chain having SEQ ID NO:27 or at least 85% sequence identity thereto; - a light chain having SEQ ID NO:28 or at least 85% sequence identity thereto and a heavy chain having SEQ ID NO:29 or at least 85% sequence identity thereto; - a light chain having SEQ ID NO:30 or at least 85% sequence identity thereto and a heavy chain having SEQ ID NO:31 or at least 85% sequence identity thereto; - a light chain having SEQ ID NO:32 or at least 85% sequence identity thereto and a heavy chain having SEQ ID NO:33 or at least 85% sequence identity thereto; - or a light chain having SEQ ID NO:34 or at least 85% sequence identity thereto and a heavy chain having SEQ ID NO:35 or at least 85% sequence identity thereto.
Antibody with a variant Fc domain
The antibody comprises a variant Fc domain, expanding its potential function or characteristics as compared to a native Fc domain.
Monoclonal antibody forms and engineered variants
The antibody is specified as a monoclonal antibody, and can be selected from chimeric, human, humanized, recombinant, engineered, conjugated, bispecific monoclonal antibodies, or fragments thereof.
Immunoconjugate antibody comprising a therapeutic agent and linker
The antibody is an immunoconjugate that includes a therapeutic agent selected from the group consisting of a pharmacologic agent, a radioisotope, or a toxin, and additionally includes a linker, enabling targeted delivery.
The inventive features center on specifically defined antibodies targeting CLPTM1L, their particular sequences and forms, and their use in various compositions or as immunoconjugates for therapeutic application.
Stated Advantages
The invention allows for the treatment or prevention of cancers, solid tumors, and pre-neoplastic lesions associated with CLPTM1L protein dysfunction.
The provided antibodies and compositions sensitize tumor cells to chemotherapeutic agents, reversing or overcoming drug resistance.
Compositions inhibit tumor growth, reduce tumor volume, and curb metastasis by targeting tumor survival signaling pathways.
The antibodies exhibit specificity for tumor tissue with little to no binding to normal or benign tissues, offering tumor selectivity.
The immunoconjugate forms permit targeted delivery of therapeutic agents such as toxins or pharmacologic agents, which can increase efficacy and reduce side effects.
Documented Applications
Treatment and prevention of cancer, including solid tumors and pre-cancerous lesions, associated with CLPTM1L/CRR9 protein dysfunction.
Use in chemosensitization of tumor cells to chemotherapeutic agents, including in refractory or resistant tumors.
Pharmaceutical compositions comprising the antibodies for administration to subjects at risk of, diagnosed with, or exhibiting symptoms of tumors such as glioblastoma, sarcoma, carcinoma, lymphoma, and cancers of lung, pancreas, prostate, skin, bladder, kidney, ovary, colon, colorectal region, breast, cervix, brain, esophagus, and stomach.
Use in immunoconjugates for targeted delivery of toxins, radioisotopes, or pharmacologic agents to tumor cells.
Diagnostic, theranostic imaging, and molecular imaging via antibody-conjugated nanoparticles in biomedical applications, including in vivo diagnosis and targeted drug delivery.
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